Abstract
Nitric oxide (NO) is a crucial factor for the integrity and function of the endothelium. Besides its role in blood pressure regulation, NO acts antithrombotically and antiapoptotically. The laminar flow in the blood vessel, called shear stress, is the most potent endogenous protective force against endothelial cell apoptosis, mostly by increasing the expression of the endothelial NO synthase (eNOS) and thereby increasing NO bioavailability in endothelial cells. However, during the process of endothelial cell aging, shear stress is unable to induce eNOS expression and protect against apoptosis induction. Moreover, apoptosis induction is correlated with aging in vivo, suggesting a link between NO bioavailability, aging, and apoptosis. Moreover, cellular aging is accompanied with an increase in reactive oxygen species (ROS), which results in an imbalance of the redox status of the cell. Thioredoxin is an important redox regulator in endothelial cells and can “bind” NO. S-nitrosylation of thioredoxin increases its enzymatic activity, which in turn leads to reduced intracellular ROS and apoptosis, suggesting that thioredoxin may play an important role in NO bioavailability. One crucial step in the process of cellular aging is the telomerase activity that is reduced in aged endothelial cells. NO can inhibit the decrease in telomerase activity and thereby delay the onset of replicative senescence. Thus, the reduction in NO bioavailability is a crucial factor for endothelial cell aging and apoptosis.
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References
Ross R (1995) Cell biology of atherosclerosis. Annu Rev Physiol 57:791–804
Hoffmann J, Haendeler J, Aicher A, Rossig L, Vasa M, Zeiher AM, Dimmeler S (2001) Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide. Circ Res 89:709–715
Miyashiro JK, Poppa V, Berk BC (1997) Flow-induced vascular remodeling in the rat carotid artery diminishes with age. Circ Res 81:311–319
Harrison DG (1994) Endothelial dysfunction in atherosclerosis. Basic Res Cardiol 1:87–102
Dimmeler S, Zeiher AM (1999) Nitric oxide—an endothelial cell survival factor. Cell Death Differ 6:964–968
Murohara T, Witzenbichler B, Spyridopoulos I, Asahara T, Ding B, Sullivan A, Losordo DW, Isner JM (1999) Role of endothelial nitric oxide synthase in endothelial cell migration. Arterioscler Thromb Vasc Biol 19:1156–1161
Tsao PS, Cooke JP (1998) Endothelial alterations in hypercholesterolemia: more than simply vasodilator dysfunction. J Cardiovasc Pharmacol 32(Suppl 3):S48–S53
Nathan C, Xie QW (1994) Regulation of biosynthesis of nitric oxide. J Biol Chem 269:13725–13728
Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377:239–242
Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, Kearney M, Chen D, Symes JF, Fishman MC, Huang PL, Isner JM (1998) Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest 101:2567–2578
Moroi M, Zhang L, Yasuda T, Virmani R, Gold HK, Fishman MC, Huang PL (1998) Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular responses to injury in mice. J Clin Invest 101:1225–1232
Schachinger V, Britten MB, Zeiher AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101:1899–1906
Fujita N, Manabe H, Yoshida N, Matsumoto N, Ochiai J, Masui Y, Uemura M, Naito Y, Yoshikawa T (2000) Inhibition of angiotensin-converting enzyme protects endothelial cell against hypoxia/reoxygenation injury. Biofactors 11:257–266
Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM (1997) Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circ Res 81:970–976
Kontush A, Chancharme L, Escargueil-Blanc I, Therond P, Salvayre R, Negre-Salvayre A, Chapman MJ (2003) Mildly oxidized LDL particle subspecies are distinct in their capacity to induce apoptosis in endothelial cells: role of lipid hydroperoxides. FASEB J 17:88–90
Dimmeler S, Haendeler J, Galle J, Zeiher AM (1997) Oxidized low density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases: a mechanistic clue to the response to injury hypothesis. Circulation 95:1760–1763
Harada-Shiba M, Kinoshita M, Kamido H, Shimokado K (1998) Oxidized low density lipoprotein induces apoptosis in cultured human umbilical vein endothelial cells by common and unique mechanisms. J Biol Chem 273:9681–9687
Sudoh N, Toba K, Akishita M, Ako J, Hashimoto M, Iijima K, Kim S, Liang YQ, Ohike Y, Watanabe T, Yamazaki I, Yoshizumi M, Eto M, Ouchi Y (2001) Estrogen prevents oxidative stress-induced endothelial cell apoptosis in rats. Circulation 103:724–729
Haendeler J, Hoffmann J, Tischler V, Berk BC, Zeiher AM, Dimmeler S (2002) Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69. Nat Cell Biol 4:743–749
Tschudi MR, Barton M, Bersinger NA, Moreau P, Cosentino F, Noll G, Malinski T, Luscher TF (1996) Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery. J Clin Invest 98:899–905
Zeiher AM, Drexler H, Saurbier B, Just H (1993) Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 92:652–662
Asai K, Kudej RK, Shen YT, Yang GP, Takagi G, Kudej AB, Geng YJ, Sato N, Nazareno JB, Vatner DE, Natividad F, Bishop SP, Vatner SF (2000) Peripheral vascular endothelial dysfunction and apoptosis in old monkeys. Arterioscler Thromb Vasc Biol 20:1493–1499
Fournet-Bourguignon MP, Castedo-Delrieu M, Bidouard JP, Leonce S, Saboureau D, Delescluse I, Vilaine JP, Vanhoutte PM (2000) Phenotypic and functional changes in regenerated porcine coronary endothelial cells: increased uptake of modified LDL and reduced production of NO. Circ Res 86:854–861
Fenton M, Barker S, Kurz DJ, Erusalimsky JD (2001) Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries. Arterioscler Thromb Vasc Biol 21:220–226
Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399:597–601
Dimmeler S, Fisslthaler B, Fleming I, Hermann C, Busse R, Zeiher AM (1999) Activation of nitric oxide synthase in endothelial cells via Akt-dependent phosphorylation. Nature 399:601–605
Chou TC, Yen MH, Li CY, Ding YA (1998) Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension 31:643–648
Wilcox JN, Subramanian RR, Sundell CL, Tracey WR, Pollock JS, Harrison DG, Marsden PA (1997) Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 17:2479–2488
Kerr S, Brosnan MJ, McIntyre M, Reid JL, Dominiczak AF, Hamilton CA (1999) Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium. Hypertension 33:1353–1358
White CR, Brock TA, Chang LY, Crapo J, Briscoe P, Ku D, Bradley WA, Gianturco SH, Gore J, Freeman BA, Tarpey MM (1994) Superoxide and peroxynitrite in atherosclerosis. Proc Natl Acad Sci U S A 91:1044–1048
Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247
Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, Dimmeler S (2004) Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res 94:768–775
van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Luscher TF (2000) Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 192:1731–1744
Nagata S (1997) Apoptosis by death factor. Cell 88:355–365
Dimmeler S, Haendeler J, Nehls M, Zeiher AM (1997) Suppression of apoptosis by nitric oxide via inhibition of ICE-like and CPP32-like proteases. J Exp Med 185:601–608
Li J, Billiar TR, Talanian RV, Kim YM (1997) Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem Biophys Res Commun 240:419–424
Haendeler J, Weiland U, Zeiher AM, Dimmeler S (1997) Effects of redox-related congeners on apoptosis and caspase-3 activity. Nitric Oxide 1:282–293
Holmgren A (1989) Thioredoxin and glutaredoxin systems. J Biol Chem 264:13963–13966
Holmgren A (2000) Antioxidant function of thioredoxin and glutaredoxin systems. Antioxid Redox Signal 2:811–820
Greider CW (1996) Telomere length regulation. Annu Rev Biochem 65:337–365
Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43:405–413
Vasa M, Breitschopf K, Zeiher AM, Dimmeler S (2000) Nitric oxide activates telomerase and delays endothelial cell senescence. Circ Res 87:540–542
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Haendeler, J. Nitric oxide and endothelial cell aging. Eur J Clin Pharmacol 62 (Suppl 1), 137–140 (2006). https://doi.org/10.1007/s00228-005-0008-8
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DOI: https://doi.org/10.1007/s00228-005-0008-8